Innate and Adaptive Cytokines: Functions and Mechanisms

Innate Cytokines

Cytokines I (Innate): Redundant (same), synergistic (+), or antagonistic.

Interferons

Interferons: IFN (alpha, omega, tau, beta), Type I and Type II range.

Type I: Antiviral, inhibits protein synthesis, activates NK cells, expresses MHC class I to activate CD8, and inhibits mitosis.

Cytokine Alarm and Interleukins

Cytokines alarm:

• IL-1: All cells, viral defense, tumor response.
• IL-6: Produced by T cells, macrophages, endothelial cells, and fibroblasts. Includes IL-1Ra (inflammatory/anti-inflammatory), secreted by myocytes (muscle). Regulates B cell differentiation and antibody synthesis.
• TNF: Produced by T cells, macrophages, and NK cells. Effects include vascular permeability, endothelial activation, fever, acute phase proteins, and in severe cases, septic shock and death.

IL-15: Development and activation of NK cells.

IL-12: T cell and NK cell activation, and CD8 differentiation to Th1.

Chemokines

Chemokines:

• CCK: Produced by cells, attracts and activates NK cells, lymphocytes, and basophils.
• Macrophage-activating chemokines and CXCL produced by neutrophils.

Adaptive Cytokines

Cytokines II (Adaptive):

IL-2: Produced by CD4 Th1 cells. Acts as an autocrine proliferation factor (clonal expansion), anti-apoptotic (bcl-2) and ultimately pro-apoptotic. Stimulates the cytotoxic activity of NK and CD8 cells, and the growth and proliferation of B lymphocytes.

Superantigen and Toxic Shock: Secondary T cells, macrophages, TNF, super-lethal septic shock, Gram-negative infections, primary macrophage TNF response.

IL-4: Produced by CD4 Th2 cells, eosinophils, and mast cells. Activated NK, NKT, and T cells. Clonal proliferation of B lymphocytes, class switching to IgE against allergies and helminths, and expression of MHC class II.

IFN-gamma (Type II): Produced by CD4 Th1, CD8 T cells, and NK cells. Inhibits Th2 cells. Principal activator of macrophages, induces MHC class I and II expression, and switches to antiviral IgG.

Lymphotoxin (TNF-beta): Secreted by CD4 Th1 cells or expressed on the membrane (soluble). Proinflammatory, involved in embryological lymph node development.

IL-5: Produced by CD4 Th2 and activated mast cells. Promotes IgA B cell proliferation and class switching, activation, and proliferation of cytotoxic function against helminths and eosinophils.

Hematopoietic Cytokines

Hematopoietic cytokines:

• SCF C-kit: Hematopoietic stem cells.
• IL-7: Precursor T and B cell growth and hematopoietic factor.
• IL-3: Growth factor.

T Helper Cell Responses

Th1: IL-2, IFN-gamma, lymphotoxin. Cellular response (neutrophils, macrophages, CD8, NK, B cells), targets intracellular viruses.

Th2: IL-4, IL-5, IL-10, IL-13. Humoral response, targets extracellular bacteria.

Cytotoxicity and Immune Effector Mechanisms

CD8 and NKT Lymphocytes: Granule-dependent activation via TCR and calcium (Ca2+) / FAS / FASL pathway.

CD4 T Lymphocytes: FAS / FASL pathway, cytotoxic cytokines TNF and lymphotoxin.

NK Cells: Granules (Ca2+), FAS / FASL, and antibody-dependent cellular cytotoxicity (ADCC) mediated by IgG.

Macrophages and Neutrophils: PRR phagocytosis of PAMPs, cell lysis (free radical nitric oxide - NO), and IgG-mediated ADCC.

Eosinophils: Cell lysis via toxins and ADCC using IgE (against helminths).

Key Immune Mediators

Perforin: Similar structure in CD8 (inducible) and NK/NKT cells (constitutive).

FAS / FASL in T cells: Death domains and activation of caspases to nucleate NK, NKT, and CD8 cells. CD4 cells also utilize TNF and lymphotoxin.

Activation and Inhibition: CD8 TCR activation / MHC class I inhibits NK cells.

ADCC: IgG antibodies bind Fc receptors to activate NK cells and release granules.

NKT Cells: Express NK1.1 and TCR-CD1 presenting molecules.

Macrophages and Neutrophils: Phagocytosis and IgG-mediated ADCC. Their granules contain nitrogen-based free radicals (distinct granule type).